Penicillin salts of methylpentylamine



Patented Aug. 4, 1953 PENICILLIN SALTS OF METHYL- PENTYLAMI NE Vernon V. Young, Terre Haute, Ind., assignor to Commercial Solvents Corporation, Terre Haute, Ind., a corporation of Maryland I No Drawing. ApplicationFebi-uary 3, 1950, Serial No. 142,355,

4 Claims." (01. 260-2391) This invention relates tosalts of penicillin and more particularly relates to the penicillin salt of three isomers of (methylpentyl)amine.

All penicillin salts are not practical for therapeutic use. For example, a penicillin salt may not be stable at ordinary temperatures and thus in order for the therapeutic activity of the salt to be retained, it must be refrigerated during storage or else rapid deterioration of the therapeutic activity occurs. Some penicillin salts are too toxic for use therapeutically and hence must be ruled out-completely. g

In addition to the stabilityand toxicity characteristics of penicillin salts consideration must also be given to their solubility properties. expression of favorable solubility properties is found in the measurement of blood levels of the penicillin at intervals after injection into or ingestion by the body. The longer penicillin can be found in the blood after it has been placed in the body, the more effective it is against pathogenic organisms present in the body provided they are penicillin susceptible. If, however, higher blood levels of penicillin are only maintained for short periods after injection or ingestion of the penicillin salt, the penicillin content of the salt is largely wasted and there is little or no alleviation of the pathologic condition being treated unless there are repeated administrations of the penicillin at short intervals.

The object of the present invention is to provide stable penicillin salt compositions of low The toxicity which give prolonged blood levels of I penicillin whether given orally or by injection.

vI have now discovered stable penicillin salts possessing low toxicity characteristics which give prolonged blood levels after being injected into the body or after being administered orally. My new compositions are the penicillin salts of the isomers (1 methylpentyhamine, (2 methylpentyl) amine, and (l-methylisopentyl) amine.

My new compositions can be prepared by mixing one equivalent of a water-soluble penicillin salt such as potassium penicillin in aqueous solution with one equivalent of (l-methylpentyD- amine hydrochloride, (Z-methylpentyl) amine hydrochloride or (l-methylisopentyDamine hydrochloride as the case may be in aqueous solution. The penicillin salt precipitated from the aqueous solution is recovered therefrom by filtration and dried.

(Penicillin salt of (l-methylpentyl) amine: Nitrogen analysis Calc; 9.65; found 9.36. Penicillinsalt of (2-methylpentyl) amine: Nitrogen analysis-Cale. 9.65; found 9.31. Penicillin salt of (l-methylisopentyl)amine: Nitrogenamilysis-Cale. 9.65; found 9.26.)

Blood level tests were conducted wherein my new penicillin salts of (l-methylpentybamin'e, (2 methylpentyDamine, and (1 methylisopentyl) amine were given orally, and injected intramuscularly into dogs, the amount of penicillin in the blood stream being measured at definite intervals after administration. The following table shows the blood levels obtained after a portion of my new penicillin salt of (l-methylpentyl) amine containing 100,000 unitsof penicillin was administered orally.

Table I [Penicillin salt of (l nethylpentyllamine; oral administration- 100,000 units/dog; units penicillin/ml. blood.]

Hours 7 Dog No. Remarks U 750 190 081 O Tablet 0 750 .185 038 0 D0. 0 820 300 074 0 D0. 0 1. 380 059 0 D0. 0 1. 0O 620 0 D0. 0 725 274 147 0 D0.

7 The following table indicatesblood levels ob tained when my new penicillin salt of (2-methylpent'yliamine was administered orally, 100,000

[Penicillin salt of (2-ruethylpentyl)amine; oral administration- 100,000 units/dog; units penicillin/m1. blood.]

Hours Dog 0. Remarks l. 26 059 058 Tablet. 1. D

QOOOOOQ The following table is ofiered for comparison 3 purposes. It shows blood levels obtained when procaine penicillin was administered orally, 100,000 units of penicillin being administered to each dog. Procaine penicillin is presently accepted as being the best form of the antibiotic.

Table III [Procaine penicillin; oral administration-100,000 units/dog; units penicillin/ml. blood.]

V, and VI that my new compounds give longer and more consistent blood levels when administered as a suspension in oil than the presently considered best known form of the antibiotic.

The following table indicates blood levels obtained when my new penicillin salt of (2-methylpentyl) amine was injected intramuscularly as an aqueous suspension, 60,000 units of penicillin being injected into each dog.

I Hours Table VII Dog 7 7 Remarks KZ-methylpentyhamina; intramusculariy-aqueous suspension 0 2 4 6 8 60,000 units/dog; unitspeniciIlln/rnl. blood.]

0 g 140 8 031 Tight Hours 0 O. ,P' o 0. 790 o. 029 0. 068 z 0 Do. 0 0. 180 O. 024 0 U D'O. O 1 2 6 O 1. 98 0. 480 0.106 0 D0. 0 0. 710 0. 191 0.112 0.109 D0.

77 O 2. 57 0. 220 U r 7 0 3. 80 1. 23 0 It can be seen from a comparison of the tables giving data on blood levels obtained after oral administration of the various salts of penicillin, that my new compounds give more consistent blood levels than the present best known form of penicillin.

,The followin "table indicates blood levels obtained when my new penicillin salt of (l-methyl- .pentyhamine was injected intramuscularly as a suspension in peanut oil, 60,000 units of penicillin being injected into the dog.

Table IV [(l-mthylpentyDamine; intramuscularlyoil suspension60,000 units/dog; units penicillin/ml. blood.]

Hours Dog No.

The lollowing table indicates blood levels obtained when my new penicillin salt of (l-methylisopentyl) amine was injected intramuscularly as a suspension in peanut oil, 60,000 units of penicil- The 'following 'table is offered for comparison purposes also. It shows blood levels obtained when procaine penicillin was administered intramuscularly as a susp'ensionin peanut oil, 60,000 units of penicillin being injected into each dog.

Table VI ine enicillin; intramuscula'rly-oil suspension-60,000 units/ [Prom p dog; units penicillin/m1. blood.]

Hours Dog No.

-It can be seen'iroma comparisonpf-Tables-IV,

The following table indicates blood levels obtained when my new penicillin salt of (l-methylisopentyDamine was injected intramuscularly as an aqueous suspension, 60,000 units of penicillin being injected into each dog.

Table VIII [(l-methylisopentyl)amine; intra1nuscularlyaqueous suspension- 60,000 units/dog; units penicillin/ml. blood.]

Hours Dog No.

Table IX [Toxic!ty(i-methylpentyl)nmine.]

LDg LDsa L ino mg. of salt/kg. of body weight of test mice Intrapcritoneally 260120 400 subcutaneously 200 860 l, 000

The following table shows results of toxicity tests of my new penicillin salt of (2-methylpentyDamine, the tests having been conducted on mice asshown above for Table IX.

Table X [Toxicity-(Z-methylpentyl)amine] LDo LDsn LDlW mg. of salt/kg. or body weight of test mice lntraperltoneolly 250 480i43 600 subcutaneously-- 200 8105;143 1,600

The following table shows results of toxicity .tests oi mynew penicillin salt of -(1-methyliaosubcutaneously pentyl) amine, the tests having been conducted on mice as shown above for Tables IX and X.

Table XI [Toxicity-(l-methylisopeutyl)amine] mg. salt/kg. of body weight of test mice Intraperitoneally 550 The following table shows results of toxicity tests of procaine penicillin, the tests having been conducted on mice as shown above for Tables IX and XI.

Table XII [Toxicityprocaina] LDo LDw L lou mg. of salt/kg. of body weight 0! st mice Intraperitoneally 200 440i28 550 subcutaneously l, 600 1, 1, 600

From the above 12 tables it can be seen that my new compounds are distinct improvements over procaine penicillin which is considered to be the References Cited in the tile 01 this patent UNITED STATES PATENTS Number Name Date 2,493,625 Goldberg et a1. Jan. 3, 1950 2,527,810 Goldberg et al Oct. 31, 1950 2,547,640 Goldman Apr. 3, 1951 OTHER REFERENCES British Report CMR-Br. 234, PB 79927, Dec.

5, 1947, page 3.

Physicians Bulletin, Nov.-Dec. 1945, page 183. 

1. THE PENICILLIN SALT OF A COMPOUND SELECTED FROM THE GROUP CONSISTING OF (1-METHYLPENTYL)AMINE, (2-METHYLPENTYL) AMINE, AND (1-METHYLISOPENTYL) AMINE. 